Injectable depot formulation comprising crystals of iloperidone

ABSTRACT

An injectable depot formulation comprising crystals having Structure (I) wherein R is (FII) and the X 50  value of the crystals is from 1 to 200 microns. Depot formulations containing crystals of iloperidone or its metabolite have the following advantages: (i) release of the crystals in plasma can be correlated with the size of the crystals; (ii) absorption of the crystals in plasma can be correlated with the size of the crystals; (iii) the particle size of the crystals can be controlled by crystal engineering and/or milling; and (iv) the crystals are stable upon storage, and stable to sterilization procedures, such as gamma irradiation.

FIELD OF THE INVENTION

This invention relates to an injectable depot formulation comprisingcrystals of iloperidone or its metabolite wherein the release andabsorption of the crystals in plasma can be correlated with the crystalsize.

BACKGROUND OF THE INVENTION

The controlled release of an active agent frompoly(d,l-lactide-co-glycolide) microspheres and the general status ofsuch lactide use is discussed in the article “Controlled Release of aLuteininizing Hormone-Releasing Hormone Analogue fromPoly(d,l,-lactide-co-glycolide) Microspheres” by L. M. Sanders et al.,J. of Pharm. Sci., 73, No. 9, September (1984).

Microencapsulated depot formulations of iloperidone and a poly-glycolidepolylactide glucose star polymer are disclosed in U.S. PatentApplication Nos. 60/339,036, filed Oct. 30, 2001, and 60/339,037, filedOct. 30, 2001.

U.S. Pat. No. 5,955,459 describes compositions for treatingschizophrenia containing conjugates of a fatty acid and iloperidone. Apreferred fatty acid is cis-docosahexanoic acid.

It would be advantageous to develop an iloperidone or its metabolitedepot formulation that is, as chemically-pure as possible, and which isstable to sterilization procedures, such as gamma irradiation.Furthermore, the depot formulation should provide a reliable,reproducible and constant plasma concentration profile of iloperidone orits metabolite following administration to a patient.

SUMMARY OF THE INVENTION

The present invention provides an injectable depot formulationcomprising crystals of iloperidone or its metabolite or apharmaceutically acceptable salt, hydrate, solvate, polymorph andstereoisomer thereof, wherein the mean particle size (X₅₀ value) of thecrystals is from 1 to 200 microns.

According to another aspect the invention provides an injectable depotformulation comprising crystals having Structure (I)

wherein R is

and the X₅₀ value of the crystals is from 1 to 200 microns.

According to a further aspect the invention provides crystals ofiloperidone or its metabolite or a pharmaceutically acceptable salt,hydrate, solvate, polymorph and stereoisomer thereof, wherein the X₅₀value of the crystals is from 1 to 200 microns.

The present inventors have unexpectedly determined that depotformulations containing crystals of iloperidone or its metabolite havethe following advantages: (i) release of the crystals in plasma can becorrelated with the size of the crystals; (ii) absorption of thecrystals in plasma can be correlated with the size of the crystals;(iii) the particle size of the crystals can be controlled by crystalengineering and/or milling; and (iv) the crystals are stable uponstorage, and stable to sterilization procedures, such as gammairradiation.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photomicrograph of iloperidone crystals wherein 1 grid isequal to 100 microns.

FIG. 2 is a photomicrograph of iloperidone crystals after millingwherein 1 grid is equal to 250 microns.

FIG. 3 is a graph of mean plasma concentrations in female rabbits of aniloperidone crystal depot formulation having an X₅₀ value of 16 micronsand 30 microns over a period of time.

FIG. 4 is a graph of mean plasma concentrations in female rabbits of aniloperidone crystal depot formulation having an X₅₀ value of 170 micronsover a period of time.

DESCRIPTION OF THE INVENTION

Iloperidone is1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone.As used herein, “iloperidone” includes any salts, hydrates, solvates,polymorphs such as amorphous polymorphs, and/or stereoisomers thereof.The metabolite of iloperidone is1-[4-[3-[4-(6-fluoro(d)isoxazol-3-yl)-piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanol.As used herein, “metabolite of iloperidone” includes any salts,hydrates, solvates, polymorphs such as amorphous polymorphs, and/orstereoisomers thereof.

Preferably, the crystals have Structure (I)

wherein R is

It is noted that when R is

the crystals may exist as either the (R) or (S) enantiomer, or as aracemic mixture thereof. The (S) enantiomer has Structure II

The (R) enantiomer has Structure (III)

The crystals may be in the form of needles, trigonal forms, tetragonalforms, flat rod shaped, cubes, parallelepipeds, or plate-like. The meanparticle size (X₅₀ value) of the crystals is preferably from about 1 toabout 200 microns, more preferably 10 to 170 microns, wherebyapplication of the depot formulation to a patient can be carried outusing a standard gauge (typically 18 or 20 gauge) needle. Mostpreferably, the mean particle size (X₅₀ value) of the crystals is from15 to 70 microns.

The crystals may be prepared by crystal growth or engineering directlyto a desired crystal size. In the alternative, the crystals may beprepared to a larger crystal size than is desired in the depotformulations. In such a situation, the crystals may be milled or groundto achieve crystals having a size in the desired range. Such a millingstep, for example, is important for achieving the desired crystal sizedistribution. In principle any mill can be used, for example, a pinmill.Following milling, the crystals may optionally be passed through ascreen stack or sieve with crystals of the desired size retained whilethe crystals falling outside of the desired range (either too small ortoo large) are discarded.

It is also within the scope of the invention to provide the depotformulations of the invention as suspensions in a suitable vehicle.Aqueous suspensions are preferred such as the crystals suspended inwater. The present inventors have determined that in the case of asuspension, the crystals are preferable administered with one or moreadditional ingredients.

Additional ingredients which may be used in the depot formulations ofthe invention include natural and/or artificial ingredients which arecommonly used to prepare pharmaceutical compositions. Examples ofadditional ingredients include a surfactant, solubilizer, emulsifier,preservative, isotonicity agent, dispersing agent, wetting agent,filler, solvent, buffer, stabilizer, lubricant, and thickening agent. Acombination of additional ingredients may also be used. Preferredadditional ingredients are a surfactant, isotonicity agent, andthickening agent. Generally, such ingredients and their concentrationsin parenteral formulations are known to those skilled in the art, andthus, only examples of the preferred additional ingredients aredescribed. The depot formulations of the invention should not be limitedto the following examples of preferred additional ingredients.

Examples of surfactants include: sorbitan fatty acid esters such assorbitan trioleate, phosphatides such as lecithin, acacia, tragacanth,polyoxyethylated sorbitan monooleate and other ethoxylated fatty acidesters of sorbitan, polyoxyalkylene derivatives of propylene glycol,such as those available under the trademark PLURONIICS, especiallyPLURONICS F68; polyoxyethylated fats, polyoxyethylatedoleotriglycerides, linolizated oleotriglycerides, polyethylene oxidecondensation products of fatty alcohols, alkylphenols or fatty acids or1-methyl-3-(2-hydroxyethyl)imidazolidone-(2). As used herein,“polyoxyethylated” means that the substances in question containpolyoxyethylene chains, the degree of polymerization of which generallyis between 2 and 40, and preferably, between 10 and 20. A preferredsurfactant is a polyoxyalkylene derivative of propylene glycol, such asPLURONICS F68 which is available from BASF.

The amount of surfactant in the depot formulations of the invention isin the range known in the art for parenteral formulations, preferablyfrom about 0.5 to about 10 mg/mL.

Examples of thickening agents include: croscarmellose sodium, sodiumcarboxymethyl cellulose, and hydroxypropyl cellulose. A preferredthickening agent is sodium carboxymethyl cellulose.

The amount of thickening agent in the depot formulations of theinvention is in the range known in the art for parenteral formulations,preferably from about 2 to about 25 mg/mL.

Examples of isotonicity agents which may impart tonicity to the depotformulations to prevent the net flow of water across a cell membrane,include: salts such as sodium chloride; sugars such as dextrose,mannitol, and lactose. Mannitol is a preferred isotonicity agent.

The amount of isotonicity agent in the depot formulations of theinvention is in the range known in the art for parenteral formulations.

The amount of iloperidone or its metabolite in the depot formulationswill vary depending upon the severity of the condition to be treated.The depot formulations of the invention are preferably injectable andmay be administered by intramuscular or subcutaneous injection. Thedepot formulations administered by injection provide an effectivetreatment of diseases over an extended period, for example, from about 2to about 8 weeks. The depot formulation allows a controlled release ofiloperidone or its metabolite by dissolution of the crystals, andtherefore, steady state levels of the iloperidone or its metabolite areobtained over the extended period.

The amount of iloperidone or its metabolite administered in oneinjection is preferably from about 10 mg to about 1000 mg. Morepreferably, the amount of iloperidone or its metabolite administered inone injection is from about 100 mg to about 750 mg.

In one embodiment of the invention, the crystals of defined size arefilled into a glass vial, purged with nitrogen and sealed with a rubberstopper. The vial may be terminal sterilized by gamma irradiation,preferably, in a range of 25-35 kGy or manufactured under asepticconditions.

In one embodiment of the invention, the iloperidone crystals areinjected into the body.

In one embodiment of the invention, the crystals of the metabolite ofiloperidone are injected into the body.

In another embodiment of the invention, the iloperidone crystals aresuspended in water, and the suspension is injected into the body.

In another embodiment of the invention, the crystals of the metaboliteof iloperidone are suspended in water, and the suspension is injectedinto the body.

The depot formulation of the invention is useful for treating centralnervous system disorders, for example, psychotic disorders such asschizophrenia. The invention also provides a package comprising acontainer containing the depot formulation and instructions for usingthe depot formulation for treating schizophrenia in a patient.

The following examples further describe the materials and methods usedin carrying out the invention. The examples are not intended to limitthe invention.

EXAMPLE 1

Preparation of1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl]-3-methoxyphenyl]ethanonehaving the structure:

Into a 2 L Erlenmeyer flask with magnetic stirrer and reflux coolerunder nitrogen atmosphere and an external temperature of 20-25° C., 250g of iloperidone and 1050 g of butylacetate, were added. The light brownsuspension was heated to an internal temperature of 80° C. until abrownish solution was formed. The solution was filtered over Cellflockinto a preheated 2.5 L glass vessel with a blade-stirrer andreflux-cooler under nitrogen atmosphere. The Erlenmeyer flask and filterwere washed with warm butylacetate (ca. 70° C.). The brownish solutionwas reheated to an internal temperature of 80° C. and stirred for 5 to10 minutes. The solution was cooled with 0.75 K/min to an internaltemperature of 65° C. and seeded with 2.5 g of iloperidone milled, whichwas suspended and ultrasonicated in 7.5 g of butylacetate.

The suspension was cooled to an internal pressure of 0° C. with a rateof 0.25 K/min and stirred for 2 to 12 hours at an internal temperatureof 0° C. The suspension was filtered over a glass nutsche (0=110 mm) for15 seconds. The filter cake (cake thickness=4 cm) was flushed withmotherliquor and 275 g of cold butylacetate (0° C.) in two portions.

Iloperidone, 315 g, was obtained as wet, light brownish filtercake. Thewet product was dried at an external temperature of 50-60° C. under avacuum of less than 2 mbar for about 16-24 hours. Iloperidone, 238.3 g,was obtained. Theoretical yield was determined to be 94.4%.

EXAMPLE 2

The iloperidone crystals prepared in Example 1, 120 mg, having aparticle size X₅₀=32 μm were reconstituted with 1 ml of a mixturecontaining sodiumcarboxymethylcellulose, Pluronics F68, and mannitol, byshaking resulting in a homogeneous suspension. The suspension waswithdrawn from the vial with a syringe and injected into rabbits.

EXAMPLE 3

The iloperidone crystals prepared in Example 1, 850 mg, having aparticle size X₅₀=15 μm were reconstituted with 2 ml of a mixturecontaining sodiumcarboxymethylcellulose, Pluronics F68, and mannitol, byshaking or swirling until a homogeneous suspension was obtained. Thispastelike suspension was withdrawn from the vial with a syringe andinjected into rabbits.

EXAMPLE 4

The iloperidone crystals prepared in Example 1, 850 mg, having aparticle size X₅₀=51 μm were reconstituted with 2 ml of a mixturecontaining sodiumcarboxymethylcellulose, Pluronics F68, and mannitol, byshaking resulting in a homogeneous suspension. The suspension waswithdrawn from the vial with a syringe and injected into rabbits.

EXAMPLE 5

Regarding the drawings, FIG. 3 is a graph of mean plasma concentrationsin female rabbits of an iloperidone crystal depot formulation having anX₅₀ value of 16 microns and 30 microns over a period of time. Theformulations were dose normalized to 20 mg of iloperidone per kg of eachrabbit. Each formulation was injected into six rabbits. FIG. 3 showsthat the depot formulations prepared with iloperidone crystals having aX₅₀=16 remained in the plasma of the rabbits for at least 16 days. Thedepot formulations prepared with iloperidone crystals having a X₅₀=30remained in the plasma of the rabbits for at least 25 days. The meandose normalized pharmacokinetic parameters of iloperidone in plasma foreach crystal size are summarized in Table I. TABLE I Actual doset_(max,d) Iloperidone C_(max,d) [d] Formulation [mg/kg] mean [ng/mL]mean median 16 um 16.7 53.2 6 30 um 17.0 35.3 9

The results in Table I and graph of FIG. 3 clearly show that the meanplasma concentration of iloperidone can be correlated with the particlesize of the iloperidone crystals.

EXAMPLE 6

Regarding the drawings, FIG. 4 is a graph of mean plasma concentrationsin female rabbits of an iloperidone crystal depot formulation having anX₅₀ value of 170 microns over a period of time. The formulations weredose normalized to 20 mg of iloperidone per kg of each rabbit. Theformulation was injected into six rabbits. FIG. 4 shows that the depotformulations prepared with iloperidone crystals having a X₅₀=170 micronsremained in the plasma of the rabbits for at least 30 days. The meandose normalized pharmacokinetic parameters of iloperidone in plasma aresummarized in Table II. TABLE II Actual dose T_(max,e) IloperidoneC_(max,e) [d] Formulation (mg/kg) Mean [ng/mL] (median) 170 um 15.7 ±1.9 37.4 ± 11.2 10.5

Depot formulations containing crystals of iloperidone or its metabolitehave the following advantages: (i) release of the crystals in plasma canbe correlated with the size of the crystals; (ii) absorption of thecrystals in plasma can be correlated with the size of the crystals;(iii) the particle size of the crystals can be controlled by crystalengineering and/or milling; and (iv) the crystals are stable uponstorage, and stable to sterilization procedures, such as gammairradiation.

While the invention has been described with particular reference tocertain embodiments thereof, it will be understood that changes andmodifications may be made by those of ordinary skill within the scopeand spirit of the following claims:

1. An injectable depot formulation comprising crystals of iloperidone orits metabolite or a pharmaceutically acceptable salt, hydrate, solvate,polymorph and stereoisomer thereof, wherein the X₅₀ value of thecrystals is from 1 to 200 microns.
 2. An injectable depot formulationcomprising crystals having Structure (I)

wherein R is

and the X₅₀ value of the crystals is from 1 to 200 microns.
 3. The depotformulation according to claim 2 wherein the crystals have Structure(II)


4. The depot formulation according to claim 2 wherein the crystals haveStructure (III)


5. The depot formulation according to claim 2 wherein the crystals are acombination of crystals having Structure (II)

and crystals having Structure (III)


6. The depot formulation according to claim 1 wherein the crystals arein a form selected from the group consisting of needles, trigonal forms,tetragonal forms, flat rod shaped, cubes, parallelepipeds, andplate-like needles.
 7. The depot formulation according to claim 1wherein the X₅₀ value of the crystals is from 10 to 170 microns.
 8. Thedepot formulation according to claim 7 wherein the X₅₀ value of thecrystals is from 15 to 70 microns.
 9. The depot formulation according toclaim 1 wherein a suitable vehicle is used to form a suspension of thecrystals.
 10. The depot formulation according to claim 9 wherein thesuitable vehicle is water.
 11. The depot formulation according to claim1 which additionally comprises an additional ingredient selected fromthe group consisting of a surfactant, solubilizer, emulsifier,preservative, isotonicity agent, dispersing agent, wetting agent,filler, solvent, buffer, stabilizer, lubricant, thickening agent, andcombinations thereof.
 12. The depot formulation according to claim 11wherein the surfactant is selected from the group consisting of asorbitan fatty acid ester, phosphatide, polyoxyethylated sorbitanmonooleate, polyoxyalkylene derivatives of propylene glycol,polyoxyethylated fat, polyoxyethylated oleotriglyceride, linolizatedoleotriglyceride, polyethylene oxide condensation products of fattyalcohol, and an alkylphenol.
 13. The depot formulation according toclaim 12 wherein the surfactant is a polyoxyalkylene derivative ofpropylene glycol.
 14. The depot formulation according to claim 11wherein the concentration of surfactant is in the range of about 0.5 toabout 10 mg/mL.
 15. The depot formulation according to claim 11 whereinthe thickening agent is selected from the group consisting of sodiumcarboxymethyl cellulose, hydroxypropyl cellulose, calcium carboxymethylcellulose, and crosslinked carboxymethyl cellulose.
 16. The depotformulation according to claim 15 wherein the thickening agent is sodiumcarboxymethylcellulose.
 17. The depot formulation according to claim 11wherein the concentration of thickening agent is in the range of about 2to about 25 mg/mL.
 18. The depot formulation according to claim 11wherein the isotonicity agent is selected from the group consisting ofsalts such as sodium chloride; sugars such as dextrose, mannitol, andlactose.
 19. The depot formulation according to claim 18 wherein theisotonicity agent is mannitol.
 20. The depot formulation according toclaim 1 wherein the amount of iloperidone or its metabolite administeredin one injection is from about 10 mg to about 1000 mg.
 21. The depotformulation according to claim 20 wherein the amount of iloperidone orits metabolite administered in one injection is from about 100 mg toabout 750 mg.
 22. A package comprising a container containing aninjectable depot formulation comprising crystals of iloperidone or itsmetabolite or a pharmaceutically acceptable salt, hydrate, solvate,polymorph and stereoisomer thereof, wherein the X₅₀ value of thecrystals is from 1 to 200 microns.
 23. A package comprising a containercontaining an injectable depot formulation comprising crystals havingStructure (I)

wherein R is

and the X₅₀ value of the crystals is from 1 to 200 microns.
 24. Crystalsof iloperidone or its metabolite or a pharmaceutically acceptable salt,hydrate, solvate, polymorph and stereoisomer thereof, wherein the X₅₀value of the crystals is from 1 to 200 microns.
 25. Crystals havingStructure (I)

wherein R is

and the X₅₀ value of the crystals is from 1 to 200 microns.